Prognostic value of pretreatment modified Glasgow Prognostic Score in small cell lung cancer: A meta-analysis

Background: The prognostic role of pretreatment modified Glasgow Prognostic Score (mGPS) in small cell lung cancer (SCLC) patients remains unclear now. Methods: The PubMed, EMBASE, Web of Science, and CNKI electronic databases were searched up to December 14, 2022. The primary and secondary outcomes were overall survival and progression-free survival, respectively. The hazard ratios (HRs) and 95% confidence intervals (CIs) were combined to assess the association between pretreatment mGPS and survival of SCLC patients. Subgroup analysis based on the country, tumor stage, treatment and comparison of mGPS were further conducted and all statistical analyses were performed by STATA 15.0 software. Results: A total of ten retrospective studies involving 2831 SCLC patients were included. The pooled results demonstrated that elevated pretreatment mGPS was significantly related to poorer overall survival (HR = 1.90, 95% CI: 1.36–2.63, P < .001) and progression-free survival (HR = 1.40, 95% CI: 1.13–1.74, P = .002). Subgroup analysis stratified by the country, tumor stage, treatment and comparison of mGPS also showed similar results. Conclusion: Pretreatment mGPS was significantly associated with prognosis in SCLC and patients with elevated mGPS experienced obviously worse survival. Thus, pretreatment mGPS could serve as a novel and reliable prognostic indicator in SCLC patients.


Introduction
Small cell lung cancer (SCLC) accounts for about 15% of all lung cancer cases. [1]4] The tumor stage of SCLC patients is usually evaluated according to the Veterans Administration Lung Study Group staging system which includes limited stage SCLC and extensive stage SCLC and about 70% of the patients are already in the extensive stage at the time of diagnosis. [2,5]] The relapse rate of SCLC after first-line treatment is certainly high and it is believed that the current staging system is not sufficient to accurately evaluate survival of SCLC patients. [9,10]herefore, a lot of indicators which might contribute to the prediction of survival of SCLC patients have been reported in the last several years such as the sarcopenia [11] and lung immune prognostic index (LIPI). [12]However, these indexes are limited in clinics due to the inconvenience and low efficiency.[15][16] Unfortunately, these continuous indicators The authors have no conflicts of interest to disclose.

All data generated or analyzed during this study are included in this published article [and its supplementary information files].
The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.All procedures performed in studies that involved human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.are unstable and there are no relatively objective criteria for clinical application.
[20][21][22] As for lung cancer, Jin et al conducted a meta-analysis to verify prognostic value of mGPS in lung cancer after including 11 studies in 2017. [23]However, they did not well identify the prognostic role of pretreatment mGPS in SCLC and the association between pretreatment mGPS and survival of SCLC patients remains unclear now.
Therefore, the aim of this meta-analysis was to further identify the prognostic value of pretreatment mGPS in SCLC, which might contribute to the survival prediction and therapy strategy formulation.

Materials and methods
This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (2020). [24]

Literature search
The PubMed, EMBASE, Web of Science and CNKI databases were searched from inception to December 14, 2022 in this meta-analysis.During the search, the following key words were used: modified Glasgow Prognostic Score, mGPS, small cell lung cancer, SCLC, prognosis, prognostic, and survival.The specific search strategy was as follows: (modified Glasgow Prognostic Score OR mGPS) AND (small cell lung cancer OR SCLC) AND (prognosis OR prognostic OR survival).To avoid omissions, the MeSH terms and free words were applied and references cited in included studies were also reviewed.

Inclusion and exclusion criteria
The inclusion criteria were as follows: (1) patients were pathologically diagnosed with SCLC; (2) the C-reactive protein and albumin levels were detected before antitumor treatments and the mGPS was classified according to the definition: C-reactive protein level ≤ 10 mg/L and albumin level ≥ 35 g/L were defined as mGPS 0, C-reactive protein level > 10 mg/L and albumin level ≥ 35 g/L were defined as mGPS 1 and C-reactive protein level > 10 mg/L and albumin level < 35 g/L were defined as mGPS 2; [17] (3) patients were divided into different groups based on the mGPS and the overall survival (OS) and (or) progression-free survival (PFS) were compared between groups; 4) the hazard ratios (HRs) and 95% confidence intervals (CIs) were reported in articles, or the Kaplan-Meier survival curves were provided.
The exclusion criteria were as follows: (1) duplicated or overlapped data; (2) meeting abstracts, letters, editorials, reviews or animal trials; (3) insufficient information to assess the methodological quality.

Data extraction
In this meta-analysis, the following information was collected from each included studies: the name of first author, publication year, country, sample size, tumor stage, treatment, comparison of mGPS, endpoints, HR, and corresponding 95% CI.

Methodological quality assessment
Due to retrospective nature of all included studies, the Newcastle-Ottawa Scale (NOS) score tool consisting of selection, comparability and outcome was applied to evaluate the quality of included studies and studies with a NOS score of 6 or higher were regarded as high-quality studies. [25]he literature search, selection, data collection, and quality assessment were all performed by 2 authors independently and all disagreements were resolved by team discussion.

Statistical analysis
All statistical analyses were conducted by STATA 15.0 software.The HRs with 95% CIs were combined to explore the association between pretreatment mGPS and OS and PFS of SCLC patients.The heterogeneity among the included studies was evaluated by I 2 statistics and Q tests.If obvious heterogeneity was detected presenting as I 2 >50% or P value <0.1, the random-effects model was used; otherwise, the fixed-effects model was applied. [26]Subgroup analysis based on the country (China vs Japan), tumor stage (mixed vs extensive stage), treatment (mixed vs chemotherapy) and comparison of mGPS (0 vs 1; 0 vs 2) were further performed.Besides, sensitivity analysis was conducted to detect the source of heterogeneity and assess the stability of pooled results.Furthermore, Begg funnel plot and Egger test were conducted to detect publication bias. [27,28]ignificant publication bias was defined as P < .05.

Basic characteristics of included studies
In overall, 2831 SCLC patients were enrolled in the analysis.With the exception of study by Winther-Larsen et al, [38] all other studies were from China or Japan.The sample size ranged from 41 to 890 and most patients received the chemotherapy.Besides, all included studies were retrospective and high-quality studies with a NOS score ≥ 6. Specific characteristics were shown in Table 1.

Sensitivity analysis and publication bias
The sensitivity analysis was conducted by excluding each included studies one by one, which indicated that the results of this meta-analysis were stable and reliable (Fig. 4).Besides, according to the symmetrical Begg funnel plot (Fig. 5) and P = .198in Egger test, no obvious publication bias was observed in our meta-analysis.

Discussion
The current meta-analysis demonstrated that pretreatment mGPS was significantly associated with survival in SCLC and patients with elevated mGPS had obviously poorer prognosis than patients with mGPS 0 did.Pretreatment mGPS could serve as a novel and reliable prognostic indicator and might contribute to the formulation of treatment strategy for SCLC patients.However, due to the limitations existed in included studies, more prospective randomized controlled trials (RCTs) are still needed to verify our results.
also manifested that an elevated mGPS predicted poor OS in patients with pancreatic cancer (HR = 1.92,P = .002). [20]Tong et al enrolled 2691 patients from 15 cohort studies and indicated that mGPS was significantly associated with OS of renal cell carcinoma (mGPS 0/1: HR = 2.64, P = .002;mGPS 0/2: HR = 3.75, P < .001). [19]s for lung cancer, only 2 meta-analyses identified the predictive role of mGPS for survival. [23]Eleven studies were included in the meta-analysis by Jin et al and their results showed that elevated mGPS was significantly related to poorer OS (mGPS 0/1: HR = 1.74,P = .001;mGPS 0/2: HR = 5.82, P = .003;mGPS 0/1-2: HR = 1.42,P = .002).However, in this meta-analysis only 3 studies focusing on SCLC patients were included and only the predictive role of mGPS for OS was investigated. [23]Meanwhile, the other meta-analysis by Yang et al just focused on NSCLC patients. [52]Due to the substantial differences in disease biological characteristics and malignant risk between SCLC and NSCLC, we believe that it is necessary to further identify prognostic value of pretreatment mGPS in SCLC, which contributes to the risk evaluation for SCLC patients.Notably, the study by Mao et al reported an opposite association between elevated mGPS and poor OS in the multivariate analysis combining the distance metastasis and mGPS. [36]However, their results of univariate analysis were consistent with our findings, which indicated that the prognostic role of mGPS might be affected by other parameters.In clinics, it is still too difficult to accurately predict the survival and therapeutic effects for SCLC due to its high malignancy and recurrence rate.Besides, the prognostic value of tumor stage (limited or extensive stage) is very limited in SCLC patients.According to our results, mGPS is verified to show high prognostic value in SCLC patients, predicting the overall prognosis and disease progression despite of the tumor stage and treatment.Therefore, mGPS might play a role in contributing to the formulation of treatment strategy and assessment of the disease progression.
Actually, there are still some field worthy of further investigations about the mGPS in SCLC.For example, it is unclear whether the change of mGPS during antitumor therapy contributes to the prediction of survival of SCLC patients.Besides, it is necessary to explore whether lowering the mGPS could improve prognosis of SCLC patients.Furthermore, a combination of mGPS and other prognostic factors might be more valuable and reliable in accurately predicting survival of SCLC patients.
There are several limitations in this meta-analysis.First, all included studies are retrospective with relatively small sample sizes, which may cause some bias.Second, most included studies are from China and Japan, which affects the generalizability of the conclusion.Third, obvious heterogeneity existed among included studies.However, we could not well identify main sources of heterogeneity based on the results of subgroup analysis.Four, due to the lack of original data, we were unable to conducted more detailed subgroup analysis based on other important parameters such as the age and comorbidity.

Conclusion
Pretreatment mGPS was significantly associated with prognosis in SCLC and patients with elevated mGPS experienced obviously worse survival.Thus, pretreatment mGPS could serve as a novel and reliable prognostic indicator in SCLC patients.However, more prospective high-quality studies are still needed to verify above findings.

Figure 1 .
Figure 1.The flow diagram of this met-analysis.

Figure 2 .
Figure 2. The association between pretreatment modified Glasgow Prognostic Score and overall survival in small cell lung cancer patients.

Figure 3 .
Figure 3.The association between pretreatment modified Glasgow Prognostic Score and progression-free survival in small cell lung cancer patients.

Figure 4 .
Figure 4. Sensitivity analysis about the association between pretreatment modified Glasgow Prognostic Score and overall survival in small cell lung cancer patients.

Table 1
Basic characteristics of included studies.

Table 2
Results of meta-analysis.